Baroreceptor and chemoreceptor reflexes are actively involved in the control of fetal blood pressure and in the maintenance of blood flow to the placenta and to the metabolizing tissues. The present project is an investigation into the mechanism of the baro-and chemoreflexes. In previous funding periods of this project, we discovered and explored the interaction between changes in fetal blood pressure and prostaglandin generation in the fetal brain. We have discovered that COX-2 expression in the brain is controlled in both site- and development- specific patterns, and that blockade of COX-2 decreases the neuroendocrine responsiveness to cerebral hypoperfusion. The expression of COX-2 is not dependent upon cellular hypoxia, but is dependent upon NMDA-glutamatergic neurotransmission. Our most recent data indicate that COX-2 is one component of an inflammatory cascade that is activated by hypoxia and cerebral hypoperfusion, and that the activation of this cascade is associated with upregulation of the apoptosis pathways. Based on these results, we have proposed three specific aims in the renewal of this project: 1) to test the hypothesis that ACTH and Arginine Vasopressin (AVP), but not autonomic nervous system responses to BCO, isocapnic hypoxic hypoxia (HH), and partial umbilical cord occlusion (UCC) are inhibited by NMDA receptor blockade and that the degree of inhibition correlates to cellular activity in brain regions and nuclei subserving sensation and integration of the reflex responses; 2) to test the hypothesis that BCO, HH, and UCC all increase inflammatory pathways in the fetal PVN, midbrain nuclei, medullary nuclei, and IML, and that the increase in inflammatory marker expression is in part dependent upon NMDA signaling; and 3) to test the hypothesis that BCO, HH, and UCC all increase apoptosis in various brain regions, and that blockade of NMDA receptors will ameliorate this outcome. In the proposed 5-year continuation of this project, we will use and innovative combination of whole animal, molecular, genomics, and informatics techniques to identify the heretofore unappreciated link between alterations in O2 and CO2, activation of NMDA-glutamatergic neurotransmission, stimulation of brain inflammation, and stimulation of cellular apoptosis and long-term impairment of brain function. The results are likely to demonstrate the importance of NMDA receptor blockade as a neuroprotective strategy in late gestation fetuses and for premature infants in the NICU.